PT100565A - NEW HETEROARILOXY-BETA-CARBOLINES, ITS PREPARATION OF MEDICINES - Google Patents

Description

1

Description relating to the patent of invention of SOHERIUG AKTIE ^ GESELLSCHAFT, German, industrial and commercial, established in Berlin and Bergkamen (postal address: 170-178 Müllerstrasse, Berlin 65), Federal Republic of Germany, (inventors: Dr. Martin Krtíger, Dr. Andreas Huth, Dr. Dieter Seidelmann, Dr. Her-bert Schneider, Dr. Lechoslaw Turski and David Fforman Stephens, residing in the Federal Republic of Germany), for " HEROES HEIEROARILOXY-F-CARBOLIOLS, ITS PREPARATION AND USE OF THE PREPARATION OF MEDICATIONS11

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION The present invention relates to a preparation of the compounds of the present invention.

EP-A-237 4-67 and EP-A-305 322 describe β-carbolines substituted by a heteroaryloxy radical which influence the central nervous system and can be used as psychoactive drugs. According to these Patent Applications it was not expected that,

of the heteroaryl substituents according to the invention, a deviation of the action profile of the compounds originated and that the compounds, due to the absence of muscle relaxation, had an improved profile of side actions.

The compounds according to the invention have

the formula I

H

in which AE represents a triazine radical optionally substituted by halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, trifluoromethyl or SC2 -R3, heteroaryl radical having 1 to 2 nitrogen atoms, condensed with a benzene ring, or represents a 5- or 6-membered heteroaryl radical having 1 to 2 nitrogen atoms, substituted by halo-gran, alkyl of 1 to 6 carbon atoms, having 1 to 6 carbon atoms, C 1 -C 6 -alkylthio, trifluoromethyl or BO 2 -E 1, R 1 represents alkyl having 1 to 4 carbon atoms or phenyl optionally substituted 1 to 2 times by alkyl having 1 to 4 carbon atoms, carbon atoms, and R 1 may be substituted one or two times, not representing the halogen substituent in the case of R 2 represents pyridine, R 4 is hydrogen, alkyl of 1 to 6 C 1 -C 6 alkoxy alkyl of 1 to 6 carbon atoms, carbon atoms in the alkoxy part and 1 to 2 carbon atoms in the alkyl part, and -

represents -O-C1-6 alkyl having 1 to 6 carbon atoms in the alkyl part, -C0 -B2, -O2,

wherein R 2 is alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, bicycloalkyl of 7 to 9 carbon atoms or a monocyclic or bicyclic aryl radical having 6 to 12 carbon atoms, optionally substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or amino,

Ra and R3 are the same or different and each represents hydrogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, - alkyl of 1 to 4 carbon atoms in the alkyl, phenyl or benzyl part,

Rc and Rc " each represents hydrogen, or together they represent a bond and R3 is cycloalkyl of 3 to 7 carbon atoms, as well as its isomers and acid addition salts. The substituent may be on ring A at positions 5-8, preferably at positions 5, 6 or 7.

Alkyl covers in each case both radicals. chain as well as branched chain, such as by -

methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl and bexyl,

Fluorine, chlorine, bromine and iodine are understood in each case.

Oxyloalkyl in each case represents cyclopropyl, cyclobutyl, cyclopentyl, skybexyl and cycloheptyl.

As the heteroaryl radical condensed with the benzene ring having 1 to 2 nitrogen atoms, mention may be made, for example, of quinoline, isoquinoline, quinoxaline or benzimidazole.

THE

If R represents a substituted nitrogen-substituted beteroaryl radical, mention is made in this quality for example of pyridine, pyrimidine, pyrazine, pyridazine and imidazole. P

By a bicycloalkyl radical R is meant bicyclolieptyl and bicyclooctyl. As the monocyclic or bicyclic aryl radical for R1, for example phenyl, bi-phenyl, naphthyl and indenyl are mentioned.

The substituents of the radical of the phenyl radical R 1 and the aryl radical R 1 may be present once or twice at any position.

As preferred variants for R4 " the quinoline, isoquinoline and quinoxaline radicals optionally substituted by halogen, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms, triazine optionally substituted once or twice by halogen, alkyl of 1 to 6 carbon atoms, carbon atoms, C1-6 alkoxy or C1-6 alkylthio, pyridazine, pyrimidine, pyrazine and pyridazine radicals substituted by alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , alkylthio of 1 to 6 carbon atoms, trifluoromethyl or SO2 -R, and pyrimidine and pyrazine radicals substituted by halogen. - 4 -

For R 2 '', C 1 -C 6 -alkyl in the alkyl moiety, -CO-R 2 'is preferred, in which R 2 has the meaning of a cycloalkyl group having 3 to 7 carbon atoms or a radical optionally substituted phenyl, and the isoxazol-3-yl radical.

The physiologically acceptable acid addition salts are derived from the known organic and inorganic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, formic, acetic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic acid, as well as alkanesulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, and the like.

The compounds of formula I, as well as their acid addition salts, due to their affinity for the benzodiazepine receptors, are usable as medicaments and exert a partially agonistic action on the known properties of the benzodiazepines, characterized in that the compounds have for example an anti-convulsive and anxiolytic action and are not atactic / muscle relaxants. For the investigation of the anxiolytic action the compounds are tested in the test of the 4 plates of harmony with the method of Boissier et al, Eur. J. Pharmacol. 4, 145-150 (1968). The table below shows the lower minimal doses (MED) that increase the locomotor activity of the bullied rat, after i.p.

PAINTING

The compound MED_mg / kg__i _.p_. A 1.56 B 0.39 - - 5 -

Isopropyl 6- (1-isoquinolyloxy) -4-methoxymethyl-β-carboline-3-carboxylate B = 6- (2,6-dimethoxy-4-pyrimidinyloxy) -4-methoxymethyl- Isopropyl 3-oarbaxylate.

Because of their effectiveness in the PT3-spasm test and the 4-plate test, the compounds of the present invention are especially useful for the treatment of epilepsy and anxiety states.

For the use of the compounds according to the invention as medicaments these are put in the form of a pharmaceutical composition containing, in addition to the active substance, inert organic or inorganic carrier substances, pharmaceutically suitable for enteral or parenteral application, such as water , gelatin, gum arabic lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.

The pharmaceutical compositions may be presented in solid form, for example as tablets, dragees, suppositories, capsules, or in liquid form, for example as solutions, suspensions or emulsions. They may optionally further contain auxiliary substances such as preservatives, stabilizers, liquefying or emulsifying agents, salts for modifying osmotic pressure or buffers.

Particularly suitable for parenteral application are solutions or suspensions for injections, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil.

Surfactant auxiliaries, such as bile acid salts, or animal or vegetable phospholipids, but also mixtures thereof, as well as liposomes or theirs, may also be used. constituents. I

For the oral application, tablets, flasks or capsules with talc and / or carrier substances or binders based on hydrocarbons such as lactose, maize starch or potato starch are suitable. The application may also be carried out in liquid form, for example as juices, to which a sweetener is optionally added.

The compounds according to the invention are administered in a unit dose of 0.05 to 100 mS of the active substance in a physiologically acceptable carrier.

The compounds according to the invention are generally applied at a dose of 0.1 to 500 mg / day, preferably 0.1 to 50 mg / day, and especially preferably 1 to 20 mg / day, for example as anxiolytics, analogously to diaze-pame. The preparation of the compounds according to the invention is carried out according to methods known per se. For example the compounds of formula I are obtained by a process consisting of

(a) reacting, with conversion into ethers, compounds of formula II

- 7 - II,

in which R 2 and R 3? have the meanings given above, with a compound of formula R 2 Y, wherein R 2 is as above and Y represents halogen or a reactive group,

or b) reacting compounds of formula III

R

00-z III,

In which R has the abovementioned meaning, R 2 represents hydrogen or EA and Z represents hydrogen, C 1 -C 4 -alkoxy or acyl reactive derivative, with an organolithium compound, optionally thereafter introduction of a blocking group in the

position 9, with obtaining compounds of formula I in Ά P

which R 4 represents -O-R 5, or c) compounds of formula IV

H-8-

Λ »Δ IX.

in which R represents hydrogen or R and R has the above meaning, with a compound of formula V

in which R 1, R 2, R 3 and R 1 have the meanings given above, in order to obtain compounds of formula I in which x

Br represents

or

compounds of formula VI

SAW,

H

Λ ·, Zj. q q

in which R represents hydrogen or R and R 1, R 2, R 3 and R 4 have the meanings indicated above, with a 5% nitrile of formula VII, in which R 5 has the meaning indicated above, compounds of formula I in which R1 represents

VII

Or

compounds of formula VIII

VII,

Wherein R 2 represents hydrogen or R 2 and R 3 have the above meaning, with a compound of the formula (R 2 CO) wherein R has the abovementioned meaning, with the proviso of compounds of formula I in which R ^ represents 0, 5

R or

f) reacting compounds of formula IX-

Λ ZL in which R 2 is hydrogen or ET, R 2 is as above and R 6 represents OH or a reactive derivative of acyl with a compound of formula

with obtaining compounds in which R1 represents

R α and then optionally dissociating blocking groups, or transesterifying the obtained compounds, or hydrolyzing the ester groups, or forming the acid addition salts, or separating the isomers. The introduction of R 3 substituent according to process variant a) is carried out according to standard methods of ether conversion which are described for example in Specification EP-A-237 467. The reactive compound of formula R 2 - Y in which Y represents for example halogen, tosylate, mesylate or tri-11

is reacted in the presence of a base such as an alcoholate or a hydroxide, or a carbonate of an alkali metal or an alkaline earth metal, in polar solvents such as dimethyl sulfoxide, dimethylformamide, acetonitrile or alcohols, at room temperature or at a higher temperature, optionally in the presence of phase transfer catalysts. The introduction of the Ή substituent? when it is -O-R according to process variant b) is carried out in the same manner as described in WO 91/09858. An alkyl or alkyl carbonyl derivative of the formula a reactive acid derivative thereof, such as carboxylimidazolide, with an organolithium compound of the formula R1 Li in polar aprotic solvents, such as cyclic or noncyclic ethers, or hydrocarbons, at temperatures ranging from -70 ° C to room temperature . At the 9-position of the β-carboline a blocking group such as a tosyl, mesyl or trialkylsilyl group may be present which is then dissociated in the final treatment of the reaction mixture, or at the end, in a customary manner, depending on the nature of the blocking group. The addition of the compounds of formulas IV and VI according to processes o) and d) is carried out according to the methods described in Specification EP-A-305 322. The addition is carried out at temperatures between 0 ° C and 40 ° C , in an aprotic solvent such as an aliphatic or cyclic ether, halogenated hydrocarbons, dimethylformamide, etc. The blocking group may optionally be used in the reaction. The blocking group is removed conventionally in the final treatment of the reaction mixture or at the end, by treatment with bases or acids, depending on the nature of the group of block. - 12 -

The preparation of the nitrile oxides is carried out, for example, by reacting β-carbolino-3-carbaldehydes with the corresponding oximes which can be converted into hydroxamic acid halides, for example with H-halogen succinimide, t- butoxy or sodium hypochlorite in the aforementioned aprotic solvents. With bases such as sodium or potassium alcoholates, trialkylamines, Hinig's base, DBU or diazabicyclooctane, the halogen hydrazide of the hydroxamic acid halides is dissociated and the nitrile oxides which are submitted to non-isolated cycloaddition (R. Annunziata et al,

Chem. Soc. 198, 529). The introduction of the oxadiazole radical according to process variants e) and f) can be carried out by the methods described in Specification EP-161 574. The preparation of 1,2,4-oxadiazol-3-yl-carbolines is carried out for example by reaction of β-carboline-3-carboxamidooximes with acid anhydrides of the formula (Râ, † -Câ, †) at a temperature ranging from room temperature to the boiling temperature of the mixture.

For the introduction of the 1,2,4-oxadiazoyl-5-yl radical, the β-carboline-3-carboxylic acid or its reactive acid derivatives, such as halides, imidazolide or mixed anhydride, cd. the alkyl carboxylates are reacted in the presence of an alcoholate with an amidooxime of formula

R 2 / HOH t v m 2 in aprotic solvents such as hydrocarbons, for example toluene, in ether or dimethylformamide, at room temperature or at a higher temperature. - 13 -

If it is desired to carry out a transesterification, the methods described in Specification EP-A-237 467 may be reacted in a transesterification reaction with alkali metal alcoholates or with the corresponding alcohol, optionally with addition of tetraisopropylate of titanium as catalyst at an elevated temperature. The introduction of the t-butyl ester group is carried out, for example, by reacting the carboxylic acid with t-butoxy-bis-dimethylaminomethane. Hydrolysis of the ester group may be carried out customarily in acidic or alkaline media, for example with sodium or potassium hydroxides in protic solvents, or according to the process described in Specification EP-A-161 574.

Mixtures of isomers may be separated into the diastereomers or enantiomers according to conventional methods, for example crystallization, chromatography or salt formation.

For the formation of the physiologically acceptable acid addition salts a compound of formula I is dissolved, for example in a little alcohol, and then reacted with a concentrated solution of the desired acid.

Where the preparation of the starting compounds is not described, they are either known or may be prepared analogously to known compounds, or by the processes described herein.

Thus for example, the preparation of the 3-carboxylates of formula II is described in Specification EP-A-130 140.

The following examples further elucidate the process of the invention. - 14 -

1.3 S of powdered potassium hydroxide are added, at room temperature, to 25 ml of dimethyl sulfoxide. Thereafter, isopropyl 6-hydroxy-β-carboline-3-carboxylate is first added to the portions and then a solution of 2 g of 1-chloroisoquinoline in 2 ml of dimethylsulfoxide After 3 hours of heating at 90-95 ° C of bath temperature there is again added 375 mg of 1-chloroisoquinoline and heated for 2 hours at 100 ° C. Pour on ice with acetic acid the pH is adjusted to the value 5, the pellet is removed by filtration and washed with ethyl acetate repeatedly. The residue is chromatographed on silica gel with methylene chloride: ethanol = 13: 1 as eluent. After concentration of the corresponding pooled fractions and recrystallization of the residue, 2.5 g (55% and theoretical yield) of 6- (1-isoquinolyloxy) -4-methoxymethyl-β-carboline-3-carboxylate isopropyl ether having a melting point of 10 ° C.

Analogously, the following are prepared:

Isopropyl 6- (4-quinolyloxy) -4-methoxymethyl-β-carboline-3-carboxylate, Melting point 165-167 ° C

Isopropyl 6- (4-methyl-2-quinolyloxy) -4-methoxymethylcarboline-3-carboxylate, m.p. 174-176 ° C

Isopropyl 6- (2-quinolyloxy) -4-methoxymethyl-3-carboline-3-carboxylate, mp 108 DEG-6- (3-chloro-2-quinoxalyloxy) -4-methoxymethyl-β-carbolino-3- -carboxylate, m.p. 223-228Â ° C.

Isopropyl 5- (1-isoquinolyloxy) -4-methoxymethyl-β-carboline-3-carboxylate, Melting point 235-237 ° C 15-

6 - (5-tosyl-2-pyridyloxy) -4-methoxymethyl-3-carboline-3-carboxylic acid isopropyl ester, mp 206-207 ° C 6- (2-tosyl-5-pyridyloxy) - 4-methoxymethyl-β-carboline-3-carboxylic acid, m.p. 206-207 ° C 6- (5-Methoxy-2-pyrazinyloxy) -4-methoxymethyl- -carboxylate, mp 18 DEG-181 DEG C. tert -Butyl 6- (5-benzoyl-2-pyrazinyloxy) -4-methoxymethyl-β-carboline-3-carboxylate, m.p. -196 ° C isopropyl 6- (2-methylmercapto-4-pyrimidinyloxy) -4-methoxymethyl-β-carbohydrazide-3-carboxylate, m.p. 209-210 ° C

Isopropyl 6- (2-methylsulfonyl-4-pyrimidinyloxy) -4-methoxymethyl-β-carboline-3-carboxylate, mp 178-179 ° C 6- (5-trifluoromethyl-2-pyridyloxy) Isopropyl 4- (2-pyrimidinyloxy) -4-methoxymethyl-β-carboline-3-carboxylate, m.p. 215-216 ° C. isopropyl, melting point 130-132Â ° C isopropyl 6- (5-t-toxo-2-pyrimidinyloxy) -4-methoxymethyl-4-carbolino-3-carboxylate, m.p. 211-212Â ° C. 4,6-dimethyl-2-pyrimidinyloxy) -4-methoxymethyl-β-ocarboline-3-carboxylate, melting point 84-85 ° C 6- 4,6-bis- (methylthio) -1,3- Isopropyl 5-triazin-2-yloxy-4-methoxymethyl-4-carboxylate, m.p. 167-170 °. 6- (2,6-dimethoxy-4-pyrimidinyloxy) -4-methoxymethyl- 3-carboxylate, melting point 159-161 ° C: 6- (4,6-dimethoxy-1,3,5-triazin-2-yloxy) -4-methoxymethyl-β-car- 3-carboxylate, mp 159 DEG-162 DEG C. 6- (1,3,5-triazin-2-yloxy) -4-m ethoxymethyl-carboline-3-carboxylate-3-carboxylate, m.p. 168-170Â ° C

Isopropyl 6- (5-methyl-2-pyrazinyloxy) -4-methoxymethyl-β-carboline-3-carboxylate,

T-butyl 6- (5-methyl-2-pyrazinyloxy) -4-methoxymethyl-β-carboline-3-carboxylate, mp 196 ° C 6- (5-methyl-2-pyrazinyloxy) -3- - (5-methylsulfinyl-3-isoxazolyl) -4-methoxymethyl-β-carboline, m.p. 194-196Â ° C

Isopropyl-6- (5-methylpyrazin-2-yl) oxy-4-ethyl-β-carboline-3-carboxylate, mp 175-177 ° C 6- (5- azino-2-yl) oxy-4-ethyl-β-carboline-3-carboxylate, mp 227-228 ° C 6- (5-bromopyrazin-2-yl) oxy- methyl-β-carboline-3-carboxylate, m.p. 245-246 ° C

Isopropyl 6- (6-methoxypyridin-2-yl) oxy-4-methoxymethyl-β-carboline-3-carboxylate, melting point 92-99 ° C

Isopropyl 6- (5-chloropyridazin-2-yl) oxy-4-methoxymethyl-β-carbolino-3-carboxylate, 2-yl) oxy-4-methoxymethyl-β-ocarboline-3-carboxylic acid, mp tb______________________________________ tb______________________________________ t-Butyl 6- (6-methoxypyridin-2-yl) butyl ester, melting point 166 ° isopropyl 5- (5-trifluoromethylpyridin-2-yl) oxy-4-methoxymethyl-β-carboelin-3-carboxylate, m.p. -trifluoromethylpyridine-2-yl) oxy-4-methoxymethyl- (Î ± -carbonyle-3-carboxylate, m.p. 178-180Â ° C.

Example 2 6- (1-isoquinolyloxy-4-methoxymethyl-3- (5-methoxyethyl) isoxazol-3-yl) p -carboline 330 mg cL 6- (1-isoquinolyloxy) -4-methoxymethyl- carboline-3-carboxylate are mixed in 10 ml of toluene with 0.62 ml of triethylamine and 0.2 g of chloro-trimethylsilane and heat at 50-60 ° G of float temperature for 45 minutes. concentration to about 6 ml 17 -

cooled to -78 ° C under argon, and 1.25 ml of a 1.2 molar solution of diisobutylaluminum hydride in hexane are added dropwise. After 30 minutes at -78Â ° C, the mixture is partitioned between 3 ml of ethanol and 0.75 ml of 1N sodium hydroxide. The mixture is further mixed with ethyl acetate and a very small amount of water. The organic phase is separated and concentrated without dehydration. The residue is triturated with hexane and yields 440 mg of 6- (1-isoquinolyloxy) -4-methoxymethyl-p- -carboline-3-carbaldehyde. 254 mg of this compound are taken which are mixed in 2.5 ml of dimethylfuran with 67.5 mg of hydroxylamine hydrochloride and 69 mg of powdered potassium hydroxide and are allowed to stand for 16 hours at room temperature. The pellet is poured onto ice and the pellet is removed by filtration, and then washed with water. 133 mg of 6- (1-isoquinolyl oxy-4-methoxymethyl-β-carboline-3-carbaldeidoxime of melting point 215-218 ° C are obtained.

450 mg of this oxime are dissolved in 7 ml of dimethylformamide and stirred at room temperature together with 218 mg of N-bromosuccinimide for 30 minutes. After the addition of 0.8 ml of triethylamine and 0.16 ml of methyl propargyl ether it is further stirred for 3 hours at room temperature. After concentration the residue is partitioned between ethyl acetate / water and the organic phase is dried, filtered and concentrated. The residue is chromatographed twice on silica gel, first with methylene chloride: ethanol = 10: 1 and then with methylene chloride: ethanol = 12: 1. After recrystallization from the corresponding pooled and concentrated fractions yields 200 mg of 6- (1-isoquinolyloxy) -4-methoxymethyl-3- (5-methoxymethylisoxazol-3-yl) -carboline having the melting point 107- 112 ° C (ethyl acetate / hexane).

Example 3 6- (1-Isoquinolyloxy) -4-methoxymethyl-3-benzoyl-β-carboline

Claims (1)

476 mg of 6- (1-isoquinolyloxy) -4-methoxymethyl-9-tosyl- p- -carboline-3-carboxylate are mixed in 10 ml of tetrahydrofuran under argon at -60 ° C with 0.79 ml of a 0.9 M solution of phenyl lithium in benzene. After one hour at -60 ° C, the mixture is stirred for 16 hours at room temperature. The preparation is acidified with glacial acetic acid and concentrated. The residue is partitioned between ethyl acetate and water and the organic phase is washed successively with saturated solutions of sodium bicarbonate and sodium chloride, is dried, filtered and concentrated. The residue is chromatographed on silica gel with methylene chloride = 10: 1. The corresponding fractions are pooled, concentrated and recrystallized. 30 mg of 6- (1-isoquinolyloxy) -4-ethoxymethyl-3-benzoyl] -pyrrolidine of melting point 159 DEG-160 DEG C. (ethyl acetate / hexane) are obtained. A compound of formula I H in which - by halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, roaryl of 1 to 2 nitrogen atoms, condensed with a benzene ring, or represents a 5- or 6-membered heteroaryl radical having 1 to 2 nitrogen atoms, substituted by halo, alkyl of 1 to 6 carbon atoms, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylthio, trifluoromethyl or SO 2 -R 3 R 4, R 1 represents alkyl having 1 to 4 phenyl atoms optionally substituted by 1 to 2 carbon atoms, carbon atom, and R ^ is unsubstituted one or two times, the halogen substituent not being represented by R representar being pyridine, R hidrog is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy-alkyl having 1 to 6 carbon atoms in alkoxy part and 1 to 2 carbon atoms in the alkyl part, and R represents -CO2-alkyl of 1 to 6 carbon atoms in the alkyl part, -O- R, b where -20 R 2 represents alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, bicycloalkyl of 7 to 9 carbon atoms or a monocyclic or bicyclic aryl radical of 6 to 12 carbon atoms, optionally substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or amino, 3L " b and R2 and R3 are the same or different and each represents hydrogen, alkoxy of 1 to 6 carbon atoms, with 1 to 6 carbon atoms, -OH 2 -O-C 1 -C 4 -alkyl in the alkyl, phenyl or benzyl part, G 1 and R 2 are each hydrogen, or together represent a bond, and R 5 represents hydrogen, alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, as well as its isomers and acid addition salts. Isopropyl 6- (1-isoquinolyloxy) -4-methoxymethylpyrrolidine-3-carboxylate, 6- (4-methyl-2-quinolyloxy) -4-methoxymethyl-β-carboline-3 isopropyl 6- (2-quinolyloxy) -4-methoxymethyl-3-carboline-3-carboxylate, 6- (3-chloro-2-quinoxalyloxy) -4-methoxymethyl-β-carbolino-3 isopropyl carboxylate, 6- (1-isoquinolyloxy) -4-methoxymethyl-3-benzoyl-β-carboline 6-isopropylcarboxylate, isopropyl 5- (2-isoquinolyloxy) -4-methoxymethyl- - (5-tosyl-2-pyridyloxy) -4-methoxymethyl-β-carboline-3-carboxylic acid 6- * isopropyl acetate - 21 * 6- (5-bromo-2-pyrazinyloxy) -4-methoxymethyl-p- 1-carboxylate 6- (2-methylmercapto-4-pyrimidinyloxy) -4-methoxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl 6- (5-bromo-2-pyrazinyloxy) -4- isopropyl 6- (2-methylsulfonyl-4-pyrimidinyloxy) -4-methoxymethyl-β-carboline-3-carboxylate isopropyl 6- (5-trifluoromethyl-2-pyridyloxy) Isopropyl 6- (4,6-dimethoxy-2-pyrimidinyloxy) -4-methoxymethyl-β-carboline-3-carboxylate isopropyl 6- (5-bromo- 2-pyrimidinyloxy) -4-methoxymethyl-β-carboline-3-carboxylate isopropyl 6- (4,6-dimethyl-2-pyrimidinyloxy) -4-methoxymethyl-p-carboline-3- 4,6-bis- (methylthio) -1,3,5-triazin-2-yloxy-4-methoxymethyl- -carboline-3-carboxylate isopropyl 6- (2,6-dimethoxy-4-pyrimidinyloxy) -4-methoxymethyl-β-carbolol-3-carboxylate 6- (4,6-Dimethoxy-1,3,5 -triazino-2-yloxy) -4-methoxymethyl-carbolino-3-carboxylate 6- (1,3,5-triazin-2-yloxy) -4-methoxymethylcarboline-3-carboxylate of isopropyl 6- (5-methyl-2-pyrazinyloxy) -4-methoxymethyl-β-carboline-3-carboxylate 6- (5-methyl-2-pyrazinyloxy) -4-methoxymethyl- (Î ± -carbonyle- T-butyl 3- (5-methyl-2-pyrazin yloxy) -3- (5-methoxymethyl-3-isoxazoyl) -4-methoxy-methyl-p-carboline, 5- (5-methylpyrazino-2- -yl) oxy-4-ethyl-β-carboline-3-carboxylic acid isopropyl ester Isopropyl 6- (5-bromopyrazin-2-yl) oxy-4-ethyl-β-carboline-3-carboxylate 6- (5-bromopyrazin-2-yl) oxy-4-methyl- isopropyl 6- (6-methoxypyridin-2-yl) oxy-4-methoxymethyl-β-carboline-3-carboxylate isopropyl 6- (5-chloropyridazin-2-yl) oxy Isopropyl 6- (5-oloropyridazin-2-yl) oxy-4-methoxymethyl-β-carboline-3-carboxylate 6- (6-methoxypyridino) -4-methoxymethyl-β-carboline-3-carboxylate -2-yl) oxy-4-methoxymethyl- (5-trifluoromethylpyridin-2-yl) -carbonyle-3-carboxylic acid isopropyl 3- (5-trifluoromethylpyridin-2-yl) oxy-4-methoxymethyl- -oxy-4-methoxymethyl-β-carboline-3-carboxylate. -inusing the compounds according to claims 1 and 2 for the preparation of medicaments. A process for the preparation of compounds of formula I, characterized in that a) compounds of the formula II are reacted with ethers, In which E and Y have the meanings given above, with a compound of formula I wherein I is as defined above and Ί is halogen or a reactive group, or b) reacting compounds of formula III -Z III, ZL in which E has the above meaning, A 1 is hydrogen or E and Z represents hydrogen, alkoxy of 1 to 4 carbon atoms or a reactive derivative of acyl with an organolithium compound optionally after the introduction of a blocking group at position 95 to obtain compoundes of formula I in which R3 represents -O-O, or o) compounds of formula IV are cyclized, R 4 , Wherein R1 represents hydrogen or R1 and R2 has the above meaning, with a compound of formula T Ra. wherein R 1, R 2, R 3 and R 4 have the meanings given above, in order to obtain compounds of formula I in which τ represents 0. or d) R a & TV compounds are cyclized of formula TI R 'to O = O * in which R 1 represents hydrogen or R 2 and R 2, R 2, R 3 and R 4 have the meanings given above, with a nitrile oxide of the formula Y 2 Ε 3 - σ 3 + -θ 2, Y 2, " E has the meaning indicated above, with the preparation of compounds of formula I in which YII, or e) cyclizing compounds of formula YIII and R 1 and R 2 have the above meaning, with a compound of the formula wherein R 2 has the abovementioned meaning, in order to obtain compounds of formula I in which R represents - And then optionally dissociating blocking groups, or transesterifying the obtained compounds, or hydrolyzing the ester groups, or forming the acid addition salts, or separating the isomers. 5. A process for the preparation of medicaments characterized in that a compound of formula I when prepared by the process of claim 4 in combination with pharmaceutical carrier substances is incorporated as the active ingredient. The applicant claims the priority of the German application filed on June 5, 1991, under Ho. P 4 118.7 ^ 1.5. Lisbon, June 4, 1992, jj, λ 1 Ή; r n '' Τ '· ι u ll · - 28 -